18-31598936-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000724044.1(ENSG00000294516):n.286-3241G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0221 in 508,938 control chromosomes in the GnomAD database, including 158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 34 hom., cov: 33)

Exomes 𝑓: 0.024 ( 124 hom. )

Consequence

ENSG00000294516
ENST00000724044.1 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.482

Publications

8 publications found

Variant links:

Genes affected

ENSG00000294516 (HGNC:):

ENSG00000294516 links:

TTR (HGNC:12405): (transthyretin) This gene encodes one of the three prealbumins, which include alpha-1-antitrypsin, transthyretin and orosomucoid. The encoded protein, transthyretin, is a homo-tetrameric carrier protein, which transports thyroid hormones in the plasma and cerebrospinal fluid. It is also involved in the transport of retinol (vitamin A) in the plasma by associating with retinol-binding protein. The protein may also be involved in other intracellular processes including proteolysis, nerve regeneration, autophagy and glucose homeostasis. Mutations in this gene are associated with amyloid deposition, predominantly affecting peripheral nerves or the heart, while a small percentage of the gene mutations are non-amyloidogenic. The mutations are implicated in the etiology of several diseases, including amyloidotic polyneuropathy, euthyroid hyperthyroxinaemia, amyloidotic vitreous opacities, cardiomyopathy, oculoleptomeningeal amyloidosis, meningocerebrovascular amyloidosis and carpal tunnel syndrome. [provided by RefSeq, Aug 2017]

TTR Gene-Disease associations (from GenCC):

amyloidosis, hereditary systemic 1
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
familial amyloid neuropathy
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hereditary ATTR amyloidosis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
heart conduction disease
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
ATTRV122I amyloidosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TTR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 18-31598936-C-T is Benign according to our data. Variant chr18-31598936-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 892146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0183 (2785/152192) while in subpopulation NFE AF = 0.0285 (1939/68014). AF 95% confidence interval is 0.0275. There are 34 homozygotes in GnomAd4. There are 1320 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 34 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124904277	XR_007066326.1 link	n.129-3241G>A		intron_variant	Intron 1 of 1
TTR	NM_000371.4 link	c.*261C>T		downstream_gene_variant		ENST00000237014.8	NP_000362.1	P02766E9KL36

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ENSG00000294516	ENST00000724044.1 link	n.286-3241G>A	intron_variant	Intron 2 of 2
TTR	ENST00000237014.8 link	c.*261C>T	downstream_gene_variant		1	NM_000371.4	ENSP00000237014.4	P02766
TTR	ENST00000649620.1 link	c.*261C>T	downstream_gene_variant				ENSP00000497927.1	P02766
TTR	ENST00000610404.5 link	c.*261C>T	downstream_gene_variant		5		ENSP00000477599.2	A0A087WT59

Frequencies

GnomAD3 genomes

AF:

0.0183

AC:

2788

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00527

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0151

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.0180

Gnomad FIN

AF:

0.0197

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0285

Gnomad OTH

AF:

0.0249

GnomAD4 exome

AF:

0.0237

AC:

8455

AN:

356746

Hom.:

124

Cov.:

AF XY:

0.0232

AC XY:

4400

AN XY:

189844

show subpopulations

African (AFR)

AF:

0.00590

AC:

AN:

10336

American (AMR)

AF:

0.0116

AC:

187

AN:

16096

Ashkenazi Jewish (ASJ)

AF:

0.0149

AC:

160

AN:

10726

East Asian (EAS)

AF:

0.000543

AC:

AN:

22100

South Asian (SAS)

AF:

0.0212

AC:

912

AN:

43066

European-Finnish (FIN)

AF:

0.0221

AC:

431

AN:

19494

Middle Eastern (MID)

AF:

0.0115

AC:

AN:

1484

European-Non Finnish (NFE)

AF:

0.0293

AC:

6231

AN:

212964

Other (OTH)

AF:

0.0217

AC:

444

AN:

20480

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

435

870

1305

1740

2175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0183

AC:

2785

AN:

152192

Hom.:

Cov.:

AF XY:

0.0177

AC XY:

1320

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.00525

AC:

218

AN:

41526

American (AMR)

AF:

0.0150

AC:

229

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

AN:

3470

East Asian (EAS)

AF:

0.000966

AC:

AN:

5178

South Asian (SAS)

AF:

0.0178

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0197

AC:

208

AN:

10576

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0285

AC:

1939

AN:

68014

Other (OTH)

AF:

0.0242

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

137

274

411

548

685

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0249

Hom.:

122

Bravo

AF:

0.0169

Asia WGS

AF:

0.00722

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Amyloidosis, hereditary systemic 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

9.7

(source)

DANN

Benign

0.75

PhyloP100

0.48

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over